Departments of Pharmacology and Biochemistry and Molecular Biology, Institute for Personalized Medicine, Penn State College of Medicine, Hershey, PA 17033, USA.Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA.

Illuminating the genomic mysteries of psychiatric diseases

Schizophrenia and bipolar disorder are complex psychiatric diseases with risks contributed by multiple genes. Studies by the PsychENCODE Consortium, including two in this issue (Chen et al. and Meng et al.), seek to elucidate the genomic elements and regulatory pathways that underpin several psychiatric disorders. Chen et al. analyzed transcriptome data from postmortem brain tissue from patients with schizophrenia or bipolar disorder. They report that the transcription factor POU3F2 is a core regulator of a gene coexpression network associated with these disorders. In a genome-wide analysis of control human brain samples from the adult and developing brain, Meng et al. report that the lncRNA DGCR5, which lies within the 22q11.2 deletion associated with schizophrenia risk, regulates expression of several SCZ-associated protein-coding genes.

Abstract

A number of studies indicate that rare copy number variations (CNVs) contribute to the risk of schizophrenia (SCZ). Most of these studies have focused on protein-coding genes residing in the CNVs. Here, we investigated long noncoding RNAs (lncRNAs) within 10 SCZ risk–associated CNV deletion regions (CNV-lncRNAs) and examined their potential contribution to SCZ risk. We used RNA sequencing transcriptome data derived from postmortem brain tissue from control individuals without psychiatric disease as part of the PsychENCODE BrainGVEX and Developmental Capstone projects. We carried out weighted gene coexpression network analysis to identify protein-coding genes coexpressed with CNV-lncRNAs in the human brain. We identified one neuronal function–related coexpression module shared by both datasets. This module contained a lncRNA called DGCR5 within the 22q11.2 CNV region, which was identified as a hub gene. Protein-coding genes associated with SCZ genome-wide association study signals, de novo mutations, or differential expression were also contained in this neuronal module. Using DGCR5 knockdown and overexpression experiments in human neural progenitor cells derived from human induced pluripotent stem cells, we identified a potential role for DGCR5 in regulating certain SCZ-related genes.